The demographic evolution in the US, with an increasing number of elderly citizens, is probably the single most important socio- economic challenge to the American health care system, both today and in the future perspective. A number of diseases associated with aging have received intense scientific attention, such as Alzheimer's disease, diabetes mellitus, Parkinson's disease, osteoporosis, and others. The aging-related motor handicap and the impaired neuromuscular function in old age, on the other hand, have received relatively less scientific interest, especially studies bridging the gap between basic science and clinical practice. This is surprising, since slowing of movements and muscle weakness are prominent features of old age in most mammals, and by far the most commonly encountered type of muscle atrophy in man is that associated with senility. Thus, improving functional independence has become an important goal as the elderly population increases, and it is well accepted that while individuals may live longer, they do not necessarily live active, happy and independent lives. This project is the first of its kind where state-of-the-art techniques are used to study the mechanisms underlying aging- related impairments in muscle function from the whole muscle to the cellular and molecular levels in humans, and how they are affected by gender. Specific interest is focused on aging- related post-translational modifications of the motor protein myosin by oxidative stress and non-enzymatic glycosylation (glycation), and the consequences of these modifications on regulation of muscle contraction. This is of significant interest since antioxidant defense system and other intracellular factors which affect glycation may become less efficient in the aged organism. The use of whole muscle, cellular- and molecular physiological methods in combination with ultrasensitive electrophoretic protein separation, imaging and immuno/enzyme- histochemical techniques offers a unique possibility to explore the regulatory and modulatory influence of the molecular motor protein myosin on contractile speed and how this regulation is affected by aging in humans. This research project will elucidate basic mechanisms underlying the motor handicap in the elderly at the skeletal muscle level and apply this knowledge to clinical research/practice, aiming to improve the quality of life and to decrease the dependency of the increasing population of elderly US citizens.